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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C231/00—Preparation of carboxylic acid amides
  • C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
• • C—CHEMISTRY; METALLURGY
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
  • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
  • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
  • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
• • C07C2102/10—
• • C—CHEMISTRY; METALLURGY
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  • C07C2602/00—Systems containing two condensed rings
  • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
  • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
  • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

• the present invention relates to a new process for the industrial synthesis of agomelatine, or N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide, of formula (I):
• Agomelatine or N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide, has valuable pharmacological properties.
• Patent specification EP 0 447 285 describes production of agomelatine in eight steps starting from 7-methoxy-1-tetralone.
• agomelatine can accordingly be synthesised in 6 steps in the course of which only one of the intermediates is isolated.
• the present invention relates to a process for the industrial synthesis of the compound of formula (I):
• R′ and R′′ which may be the same or different, each represent a linear or branched (C 1 -C 6 )alkyl group or R′ and R′′ together form a (C 2 -C 3 )alkylene chain, it being possible for the ring thereby formed to be fused with a phenyl group
• Xa represents a group —S—C(S)—OR in which R represents a linear or branched (C 1 -C 6 )alkyl group
• R, R′ and R′′ are as defined hereinbefore,
• Preferred compounds of formula (III) are:
• R represents an ethyl group.
• initiation of the free radical reactions is carried out by thermal means.
• the reaction mixture is heated to a temperature of from 50° C. to 140° C.
• Peroxides are free radical initiators that are especially suitable for carrying out the step of addition of the compound of formula (II) to the compound of formula (III), or for performing cyclisation of the compound of formula (IV) to form the compound of formula (V).
• diisobutyryl peroxide cumyl peroxyneodecanoate, tert-amyl peroxyneodecanoate, di(2-ethylhexyl) peroxydicarbonate, tert-butyl peroxyneodecanoate, dibutyl peroxydicarbonate, dicetyl peroxydicarbonate, dimyristyl peroxydicarbonate, tert-butyl peroxyneoheptanoate, tert-amyl peroxypivalate, didecanoyl peroxide, tert-amyl peroxy-2-ethylhexanoate, tert-butyl peroxyis
• the addition reaction is initiated in the presence of dilauroyl peroxide.
• reaction of cyclisation of the adduct of formula (IV) is carried out in the presence of dilauroyl peroxide optionally with dibenzoyl peroxide.
• the addition and/or cyclisation reactions are carried out in a solvent customarily used in free radical chemistry such as 1,2-dichloroethane, dichloromethane, benzene, toluene, trifluoromethylbenzene, chlorobenzene, hexane, cyclohexane, heptane, octane, ethyl acetate, tert-butyl alcohol, and mixtures thereof.
• free radical chemistry such as 1,2-dichloroethane, dichloromethane, benzene, toluene, trifluoromethylbenzene, chlorobenzene, hexane, cyclohexane, heptane, octane, ethyl acetate, tert-butyl alcohol, and mixtures thereof.
• the amine-deprotecting reaction when the amine function is protected by a phthalimide group, is carried out in the presence of a reducing agent such as sodium borohydride. Hydrazine-type agents may also be used.
• the step of aromatisation of the compound of formula (VII) may be carried out using a benzoquinone such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), whereas aromatisation of the compound of formula (VI ter ) is advantageously carried out in the presence of a strong non-nucleophilic base. This latter reaction is carried out in a polar protic medium.
• a benzoquinone such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
• DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
• aromatisation of the compound of formula (VI ter ) is carried out in the presence of an alcoholate/alcohol couple, and even more preferably in the presence of the couple potassium tert-butylate/tert-butanol or the couple potassium 3-methyl-3-pentylate/3-methyl-3-pentanol.
• Preferred compounds of formula (V) are as follows:
• Preferred compounds of formula (VI) are as follows:
• Example 5 corresponds to the same reaction route as that used in Example 4 but with the difference that only N-[2-(7-methoxy-4-oxo-1,2,3,4-tetrahydro-1-naphthyl)-ethyl]acetamide was isolated.
• Step A S-[(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-O-ethyl dithiocarbonate
• Step B S-[1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-4-(4-methoxyphenyl)-4-oxobutyl]-O-ethyl dithiocarbonate
• Step C 2-[2-(7-Methoxy-4-oxo-1,2,3,4-tetrahydro-1-naphthyl)ethyl]-1H-isoindole-1,3(2H)-dione
• Step D 4-[2-(Acetylamino)ethyl]-6-methoxy-1,2,3,4-tetrahydro-1-naphthyl acetate
• Dimethylaminopyridine (270 mg, 2.2 mmol) is then added, followed by acetic anhydride (210 ⁇ L, 2.2 mmol) dropwise.
• the solution is stirred at ambient temperature for 1 hour and then water is added.
• the pH of the solution is adjusted to from 8 to 9 by adding saturated sodium hydrogen carbonate solution.
• the aqueous phase is extracted with dichloromethane and the organic phases are washed with saturated NaCl solution, dried over magnesium sulphate, filtered and evaporated.
• the title compound is obtained after purification by flash column chromatography (ethyl acetate-petroleum ether: 90-10, then ethyl acetate-methanol: 90-10) in the form of an oil in a yield of 79%.
• Step E N-[2-(7-Methoxy-1,2-dihydro-1-naphthyl)ethyl]acetamide
• Step F N-[2-(7-Methoxy-1-naphthyl)ethyl]acetamide
• Step E To a solution of the compound obtained in Step E (100 mg, 0.41 mmol) in dichloromethane (4 mL) there is added, at ambient temperature, DDQ (111 mg, 0.49 mmol). The reaction mixture is stirred for 2 days and then washed with saturated NaHCO 3 solution. The aqueous phase is extracted with ethyl acetate, and the organic phases are collected and then dried using brine and then over MgSO 4 .
• Step A 2-[2-(7-Methoxy-4-oxo-1,2,3,4-tetrahydro-1-naphthyl)ethyl]-1H-isoindole-1,3(2H)-dione
• Step B 2-[2-(4-Chloro-7-methoxy-1,2-dihydro-1-naphthyl)ethyl]-1H-isoindole-1,3(2H)-dione
• Step C N-[2-(4-Chloro-7-methoxy-1,2-dihydro-1-naphthyl)ethyl]acetamide
• Step B To a solution of the compound obtained in Step B (370 mg, 1.0 mmol) in isopropanol (10 mL) at ambient temperature there is added sodium borohydride (190 mg, 5.0 mmol). The mixture is stirred for 3 hours under reflux, and then a solution of sodium hydroxide (80 mg, 2.0 mmol) in water (2.0 mL) is added dropwise. The mixture is maintained under reflux for 30 minutes, and then acetone (1.5 mL) is added. After 10 minutes, the mixture is cooled to ambient temperature before being concentrated under reduced pressure. The oil thereby obtained is dissolved in dichloromethane (10 mL).
• Step A 2-[2-(7-Methoxy-4-oxo-1,2,3,4-tetrahydro-1-naphthyl)ethyl]-1H-isoindole-1,3(2H)-dione
• Step B 2-[2-(4-Bromo-7-methoxy-1,2-dihydro-1-naphthyl)ethyl]-1H-isoindole-1,3(2H)-dione
• Step C N-[2-(4-Bromo-7-methoxy-1,2-dihydro-1-naphthyl)ethyl]acetamide
• Step B To a solution of the compound obtained in Step B (390 mg, 0.95 mmol) in isopropanol (10 mL) at ambient temperature there is added sodium borohydride (179 mg, 4.7 mmol). The mixture is stirred for 3 hours under reflux, and then a solution of sodium hydroxide (76 mg, 1.9 mmol) in water (2.0 mL) is added dropwise. The mixture is maintained under reflux for 30 minutes, and then acetone (1.5 mL) is added. After 10 minutes, the mixture is cooled to ambient temperature before being concentrated under reduced pressure. The oil thereby obtained is dissolved in dichloromethane (10 mL).
• Step A S-[(Acetylamino)methyl]-O-ethyl dithiocarbonate
• Acetamide (29.5 g, 0.50 mol) and paraformaldehyde (18.0 g, 0.6 mol) are dissolved in acetic anhydride (250 mL) and acetic acid (50 mL). The solution is heated at 80° C. for 5 hours, cooled and evaporated. 20% by weight of the resulting oil is then dissolved in ethanol (200 mL) and cooled to 0° C. before adding potassium O-ethylxanthate (19.2 g, 0.12 mol). The reaction mixture is stirred at ambient temperature for 6 hours, and then water is added and a large part of the ethanol is removed from the mixture under reduced pressure. The suspension is held at 0° C. for 20 minutes and filtered. After dissolving the residue in dichloromethane, the organic phase is dried over magnesium sulphate, filtered and evaporated to yield the title compound in the form of a solid in a yield of 57%.
• Step B S-[(Diacetylamino)methyl]-O-ethyl dithiocarbonate
• Step A A solution of the xanthate obtained in Step A (5.93 g, 30.7 mmol) in isoprenyl acetate (45 mL) is refluxed overnight in the presence of a few crystals of p-toluenesulphonic acid and is then cooled and concentrated under reduced pressure.
• the title compound is obtained in the form of an oil after purification by flash column chromatography (ethyl acetate-petroleum ether: 80-20) in a quantitative yield.
• Step C S-[1-[2-(Diacetylamino)ethyl]-4-(4-methoxyphenyl)-4-oxobutyl]-O-ethyl dithiocarbonate
• the compound of Step B is used directly without having been purified.
• the oil obtained in the Step above (25% by weight) is added to a solution of 1-(4-methoxyphenyl)-4-penten-1-one (2.92 g, 15.3 mmol) in ethyl acetate (8 mL) and refluxed under a nitrogen atmosphere for 15 minutes. 10 mol % dilauroyl peroxide (305 mg) are then added every 1.5 hours. After adding 2 ⁇ 10 mol % and 1 ⁇ 5 mol % dilauroyl peroxide, the solvent is evaporated off.
• the title compound is obtained after purification by flash column chromatography (ethyl acetate-petroleum ether: 90-10, then pure ethyl acetate) in the form of an oil in a yield of 72%.
• Step D N-[2-(7-methoxy-4-oxo-1,2,3,4-tetrahydro-1-naphthyl)ethyl]acetamide
• Step A S-[(Acetylamino)methyl]-O-ethyl dithiocarbonate
• Step B N-[2-(7-methoxy-4-oxo-1,2,3,4-tetrahydro-1-naphthyl)ethyl]acetamide
• the solution is refluxed under a nitrogen atmosphere for 15 minutes, and then dibenzoyl peroxide (1.53 g, 6.30 mmol) and 20 mol % dilauroyl peroxide (335 mg) are added every 1.5 hours until the reagent has completely disappeared.
• the mixture is then cooled to ambient temperature and concentrated under reduced pressure.
• the oil thereby obtained is dissolved in methanol (8.5 mL) in the presence of triethylamine (5.9 mL) and then refluxed for 1 hour.

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• 2011
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